Evidence for Domain-specific Recognition of SK and Kv Channels by MTX and HsTx1 Scorpion Toxins*
- Imed Regaya‡,
- Christine Beeton§,
- Gilles Ferrat¶,
- Nicolas Andreotti‡,
- Hervé Darbon¶,
- Michel De Waard∥ and
- Jean-Marc Sabatier‡**‡‡
- ‡CNRS Formation de Recherche Expérimentale 2738, Laboratoire de Biochimie, Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France, the §Department of Physiology and Biophysics, University of California, Irvine, California 92697, ¶Architecture et Fonction des Macromolécules Biologiques, CNRS Unité Propre de Recherche 9039, 31, Chemin Joseph Aiguier, 13402 Marseille, France, ∥Inserm U607, Commissariat à l'Energie Atomique, Institut Fédératif de Recherche 27, Département de Recherche Dynamique Cellulaire, Canaux Calciques, Fonctions et Pathologies, 17 rue des Martyrs, 38054 Grenoble Cedex 09, France, and **Laboratoire Cellpep S.A., 13-15 rue Ledru Rollin, 13015 Marseille, France
- ↵‡‡ To whom correspondence should be addressed. Tel.: 33-4-91-69-88-52; Fax: 33-4-91-65-75-95; E-mail: sabatier.jm{at}jean-roche.univ-mrs.fr.
Abstract
Maurotoxin (MTX) and HsTx1 are two scorpion toxins belonging to the α-KTx6 structural family. These 34-residue toxins, cross-linked by four disulfide bridges, share 59% sequence identity and fold along the classical α/β scaffold. Despite these structural similarities, they fully differ in their pharmacological profiles. MTX is highly active on small (SK) and intermediate (IK) conductance Ca2+-activated (K+) channels and on voltage-gated Kv1.2 channel, whereas HsTx1 potently blocks voltage-gated Kv1.1 and Kv1.3 channels only. Here, we designed and chemically produced MTX-HsTx1, a chimera of both toxins that contains the N-terminal helical region of MTX (sequence 1-16) and the C-terminal β-sheet region of HsTx1 (sequence 17-34). The three-dimensional structure of the peptide in solution was solved by 1H NMR. MTX-HsTx1 displays the activity of MTX on SK channel, whereas it exhibits the pharmacological profile of HsTx1 on Kv1.1, Kv1.2, Kv1.3, and IK channels. These data demonstrate that the helical region of MTX exerts a key role in SK channel recognition, whereas the β-sheet region of HsTx1 is crucial for activity on all other channel types tested.
- Received September 1, 2004.
- Revision received October 14, 2004.
- The American Society for Biochemistry and Molecular Biology, Inc.
